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2266. No comfort for betel-chewers
NATURAL PRODUCTS
919
Response of dogs to repeated intravenous injection of polyethylene glycol 4000 with notes on excretion and sensitization. Toxic. appl. Pharmac. 18, 35. As a result of proposals to use polyethylene glycol 4000 (PEG 4000) as a complexing agent in preparing antihaemophilic-factor concentrates for human treatment, it became necessary to assess the possible toxicity of this material after multiple intravenous injections. PEG 4000 in sterile 10~ solutions in 0"85~o aqueous sodium chloride was given in doses of 10, 30 or 90 mg/kg/day intravenously to beagles. No behavioural abnormalities developed, values for body and organ weights, haematology and biochemical studies were comparable with those of the controls and no gross or histopathological effects were observed on postmortem examination after a course of 43 injections over 2 months, 99 over 6 months or 178 over 12 months. Rapid clearance of doses of about 70 mg [I*C]PEG 4000/kg was observed in rats. The major portion of the dose, following intravenous administration, appeared in the urine within 24 hr, and within 7 days 61~ was recovered in the urine, 20~o in the faeces and none in exhaled carbon dioxide. Oral doses of PEG 4000 showed little absorption. Of the 86yo of the administered dose recovered within 7 days, most was found in the faeces together with some 4~o in the urine. Guinea-pigs given eight intradermal doses of PEG 4000 on alternate days followed by a challenge dose 3 wk later were not found to have developed any sensitivity to the compound. This result, which contrasted with earlier findings (Smyth et al. J. Am. pharm. Ass. 1950, 39, 349) was attributed to the current purification of the ethylene oxide used in the manufacture of PEG 4000. Since it is estimated that the amount of PEG 4000 administered to man in the course of treatment for haemophilia would not exceed 10 mg/kg given initially five times and subsequently three times weekly, these findings present an encouraging picture for the proposed use of this glycol in antihaemophilic-factor preparations for intravenous administration.
N A T U R A L PRODUCTS 2266. No comfort for betel-chewers Suri, K., Goldman, H. M. & Wells, H. (1971). Carcinogenic effect of a dimethyl sulphoxide extract of betel nut on the mucosa of the hamster buccal pouch. Nature, Lend. 230, 383. The chewing of betel has been suspected as being a major factor in determining the incidence of cancer of the mouth in certain areas. The metabolism of the main alkaloid, arecoline, to arecaidine could play a part in the betel nut's carcinogenic potential, if it exists, since both compounds are capable of acting as alkylating agents (Cited in F.C.T. 1970,
8, 114). In the study cited above, the right buccal pouch of hamsters was painted thrice weekly for 21 wk with dimethylsulphoxide (DMSO) extracts of betel, tobacco or both substances mixed together. Leukoplakia developed in 19 of 21 hamsters in the first group, eight of 12 in the second and 18 of 21 in the third, and tumours were found in eight of the first and 16 of the third group. No tumours occurred in animals treated with DMSO or with the extract of tobacco alone. Tumours developed about twice as rapidly with the extract of the tobacco/ betel mixture than with betel alone, and all tumours had developed by wk 18 in both groups. They were of the papillary type, were nodular in appearance and grew larger and FCT
916---K
920
NATURAL PRODUCTS
more extensively in animals treated with the mixed extract. On microscopic examination they proved to be squamous cell carcinomas with variable degrees of malignancy. No signs of metastases were found in the lymph nodes. The results of this study do not support earlier suggestions implicating either lime or tobacco, both frequently included in the betel 'quid', as the carcinogen, although a more prolonged experiment might have revealed a slower development of tumours in the animals treated with tobacco alone. No lime salts were added to any of the extracts used in this study. The findings do suggest, however, that some constituent(s) of tobacco may promote the action of a carcinogen present in the betel nut. 2267. Bracken for the black list
Pamukcu, A. M., Price, J. M. & Bryan, G. T. 0970). Assay of fractions of bracken fern (Pteris aquilina) for carcinogenic activity. Cancer Res. 30, 902. Pamukcu, A. M., Yalciner, S., Price, J. M. & Bryan, G. T. (1970). Effects of the coadministration of thiamine on the incidence of urinary bladder carcinomas in rats fed bracken fern. Cancer Res. 30, 2671. The bracken fern has much to answer for. Unwisely grazed by livestock, it has been found to induce intestinal haemorrhages and bladder tumours (Cited in F.C.T. 1970, 8, 85). Experimentally it has induced multiple ileal tumours in mice and retinopathy in sheep (ibid 1971, 9, 453). The first paper cited above describes the fractionation of extracts of fresh bracken with methanol and ether, the pelleting of the residues of the six fractions with cholesterol, and their implantation into the urinary bladder of mice. The animals were killed and examined after 52-55 wk, when a bladder-tumour incidence of 53 and 56~o was found in two groups of animals treated with methanolic-extract fractions, compared with 14~o in the control group implanted with pellets of cholesterol alone. Mice implanted with the ether and hotwater extracts showed a much lower incidence of bladder tumours. Malignant tumours were either papillary infiltrating or sessile infiltrating carcinomas. Papillomas occurred in mice of all groups, the incidence varying from 9 to 42~o. This study indicates that the carcinogens of bracken fern occur particularly in the methanol-soluble fractions. The second paper cited describes the feeding of 1 part dried bracken fern with 2 parts basic grain diet to rats for up to 12 months. One group of these rats received thiamine in a weekly subcutaneous dose of 2 mg, while the second received no thiamine treatment. A third group received neither bracken nor thiamine, but only the basic grain diet. All rats given a bracken-containing diet and surviving more than 6 months developed multiple intestinal adenomatous polyps or adenocarcinomas, but there was a marked difference between the two test groups in the incidence of bladder tumours. Only 1 l~o of males and 8~o of females receiving no thiamine developed bladder carcinomas, whereas 53~o of males and 69~o of females receiving thiamine did so. There were no intestinal or bladder tumours in the control group fed grain alone. It appears therefore that thiamine may have a marked effect on the absorption, tissue distribution, metabolism or excretion of the carcinogen of bracken fern. [Whether tumours appear in the bladder or intestine as a result of an excessive consumption of bracken, it seems extremely undesirable to continue to feed large quantities to stock, or to add bracken to the human diet, a practice which is apparently quite common in the USA, New Zealand and Japan.]
919
Response of dogs to repeated intravenous injection of polyethylene glycol 4000 with notes on excretion and sensitization. Toxic. appl. Pharmac. 18, 35. As a result of proposals to use polyethylene glycol 4000 (PEG 4000) as a complexing agent in preparing antihaemophilic-factor concentrates for human treatment, it became necessary to assess the possible toxicity of this material after multiple intravenous injections. PEG 4000 in sterile 10~ solutions in 0"85~o aqueous sodium chloride was given in doses of 10, 30 or 90 mg/kg/day intravenously to beagles. No behavioural abnormalities developed, values for body and organ weights, haematology and biochemical studies were comparable with those of the controls and no gross or histopathological effects were observed on postmortem examination after a course of 43 injections over 2 months, 99 over 6 months or 178 over 12 months. Rapid clearance of doses of about 70 mg [I*C]PEG 4000/kg was observed in rats. The major portion of the dose, following intravenous administration, appeared in the urine within 24 hr, and within 7 days 61~ was recovered in the urine, 20~o in the faeces and none in exhaled carbon dioxide. Oral doses of PEG 4000 showed little absorption. Of the 86yo of the administered dose recovered within 7 days, most was found in the faeces together with some 4~o in the urine. Guinea-pigs given eight intradermal doses of PEG 4000 on alternate days followed by a challenge dose 3 wk later were not found to have developed any sensitivity to the compound. This result, which contrasted with earlier findings (Smyth et al. J. Am. pharm. Ass. 1950, 39, 349) was attributed to the current purification of the ethylene oxide used in the manufacture of PEG 4000. Since it is estimated that the amount of PEG 4000 administered to man in the course of treatment for haemophilia would not exceed 10 mg/kg given initially five times and subsequently three times weekly, these findings present an encouraging picture for the proposed use of this glycol in antihaemophilic-factor preparations for intravenous administration.
N A T U R A L PRODUCTS 2266. No comfort for betel-chewers Suri, K., Goldman, H. M. & Wells, H. (1971). Carcinogenic effect of a dimethyl sulphoxide extract of betel nut on the mucosa of the hamster buccal pouch. Nature, Lend. 230, 383. The chewing of betel has been suspected as being a major factor in determining the incidence of cancer of the mouth in certain areas. The metabolism of the main alkaloid, arecoline, to arecaidine could play a part in the betel nut's carcinogenic potential, if it exists, since both compounds are capable of acting as alkylating agents (Cited in F.C.T. 1970,
8, 114). In the study cited above, the right buccal pouch of hamsters was painted thrice weekly for 21 wk with dimethylsulphoxide (DMSO) extracts of betel, tobacco or both substances mixed together. Leukoplakia developed in 19 of 21 hamsters in the first group, eight of 12 in the second and 18 of 21 in the third, and tumours were found in eight of the first and 16 of the third group. No tumours occurred in animals treated with DMSO or with the extract of tobacco alone. Tumours developed about twice as rapidly with the extract of the tobacco/ betel mixture than with betel alone, and all tumours had developed by wk 18 in both groups. They were of the papillary type, were nodular in appearance and grew larger and FCT
916---K
920
NATURAL PRODUCTS
more extensively in animals treated with the mixed extract. On microscopic examination they proved to be squamous cell carcinomas with variable degrees of malignancy. No signs of metastases were found in the lymph nodes. The results of this study do not support earlier suggestions implicating either lime or tobacco, both frequently included in the betel 'quid', as the carcinogen, although a more prolonged experiment might have revealed a slower development of tumours in the animals treated with tobacco alone. No lime salts were added to any of the extracts used in this study. The findings do suggest, however, that some constituent(s) of tobacco may promote the action of a carcinogen present in the betel nut. 2267. Bracken for the black list
Pamukcu, A. M., Price, J. M. & Bryan, G. T. 0970). Assay of fractions of bracken fern (Pteris aquilina) for carcinogenic activity. Cancer Res. 30, 902. Pamukcu, A. M., Yalciner, S., Price, J. M. & Bryan, G. T. (1970). Effects of the coadministration of thiamine on the incidence of urinary bladder carcinomas in rats fed bracken fern. Cancer Res. 30, 2671. The bracken fern has much to answer for. Unwisely grazed by livestock, it has been found to induce intestinal haemorrhages and bladder tumours (Cited in F.C.T. 1970, 8, 85). Experimentally it has induced multiple ileal tumours in mice and retinopathy in sheep (ibid 1971, 9, 453). The first paper cited above describes the fractionation of extracts of fresh bracken with methanol and ether, the pelleting of the residues of the six fractions with cholesterol, and their implantation into the urinary bladder of mice. The animals were killed and examined after 52-55 wk, when a bladder-tumour incidence of 53 and 56~o was found in two groups of animals treated with methanolic-extract fractions, compared with 14~o in the control group implanted with pellets of cholesterol alone. Mice implanted with the ether and hotwater extracts showed a much lower incidence of bladder tumours. Malignant tumours were either papillary infiltrating or sessile infiltrating carcinomas. Papillomas occurred in mice of all groups, the incidence varying from 9 to 42~o. This study indicates that the carcinogens of bracken fern occur particularly in the methanol-soluble fractions. The second paper cited describes the feeding of 1 part dried bracken fern with 2 parts basic grain diet to rats for up to 12 months. One group of these rats received thiamine in a weekly subcutaneous dose of 2 mg, while the second received no thiamine treatment. A third group received neither bracken nor thiamine, but only the basic grain diet. All rats given a bracken-containing diet and surviving more than 6 months developed multiple intestinal adenomatous polyps or adenocarcinomas, but there was a marked difference between the two test groups in the incidence of bladder tumours. Only 1 l~o of males and 8~o of females receiving no thiamine developed bladder carcinomas, whereas 53~o of males and 69~o of females receiving thiamine did so. There were no intestinal or bladder tumours in the control group fed grain alone. It appears therefore that thiamine may have a marked effect on the absorption, tissue distribution, metabolism or excretion of the carcinogen of bracken fern. [Whether tumours appear in the bladder or intestine as a result of an excessive consumption of bracken, it seems extremely undesirable to continue to feed large quantities to stock, or to add bracken to the human diet, a practice which is apparently quite common in the USA, New Zealand and Japan.]